This invention relates to scintigraphic scanning and more particularly to a composition and method for preparing a highly effective technetium-99m based bone-scanning agent.
For some time it has been recognized that conventional X-ray techniques are not entirely satisfactory for detecting many types of disorders at an early stage, thereby allowing effective treatment. An outstanding deficiency in X-ray examination is the inability of that technique to detect skeletal metastases in their incipient stages when meaningful treatment is possible.
Recent "bone-scanning" work for detecting metastases has been directed toward the use of radioactive isotopes, especially the isotope fluorine-18 (.sup.18 F) which is selectively migrates to the skeleton and especially to "active" sites thereon such as the joints and tumor sites where it exchanges with the hydroxyl group in calcium hydroxyapatite. .sup.18 F, however, has certain limitations due to its short half-life (110 minutes); viz., a very short "shelf life" and high energy emission which makes it unsuited for use with certain detection equipment, notably the Anger scintillation camera. Additionally, it requires very expensive equipment to prepare and is therefore quite unsuited to preparation at the site of use.
The strontium 85 isotope (.sup.85 Sr) has also been used in bone scanning, seeking the skeleton to exchange with the calcium in calcium phosphate particularly at active sites. Strontium-85 is at the opposite end of the usable half-life spectrum from .sup.18 F, having a half-life of 65 days. While this greatly increased half-life (compared to .sup.18 F) provides a desirable shelf-life, it requires that very long scan times be used to achieve a usable scan due to the low radiation emission rate.
Recently, and because of the shortcomings with the extremely short and long half-lives of .sup.18 F and .sup.85 Sr, respectively, interest has been directed to technetium-99m (.sup.99m Tc) which has a half-life of six hours. Interest in .sup.99m Tc has also increased due to the availability of convenient commercial means for generating it as needed. A .sup.99m Tc solution, in the oxidized pertechnetate (.sup.99m TcO.sub.4.sup.-) form, is obtained from commercial generators by eluting them with an isotonic saline solution (0.9% by weight of sodium chloride). One commercial generator presently available to produce a pertechnetate solution is distributed by The E. R. Squibb Company and sold under the trademark Technetope HiCon. Also, extracted .sup.99m TcO.sub.4.sup.- in isotonic saline is presently available from New England Nuclear of Boston, Massachusetts, under the designation Instant Tech.
Technetium-99m is different from either .sup.18 F or .sup.85 Sr in that it does not specifically seek or react with the skeleton. Its use therefore depends on compounding or complexing it with skeletal seeking materials. The first attempts at skeletal scanning with .sup.99m Tc utilized polyphosphates as the compounding/complexing agent and met with fair success.
Subsequent attempts to use .sup.99m Tc have involved mixing an aqueous solution of distannous-ethane-1-hydroxy-1,1-diphosphonate together with a solution of a non-stannous phosphonate. The resulting solution is then mixed with a pertechnetate to form a complex which seeks the skeleton. Such a system is reported by Yano et al. in Journal of Nuclear Medicine, Vol. 14, No. 2 at pp. 73-8, and Subramanian et al. in the Journal of Nuclear Medicine, Vol. 13, No. 12 at pp. 947-9. While this procedure has resulted in skeletal scans which are superior to those previously available, it too has shortcomings, most notably the limited stability of the distannous-ethane-1-hydroxy-1,1-diphosphonate solution.
The preparation of a soluble, stable dry system for use with a pertechnetate solution to form a bone scanning agent has met with difficulties. For instance, the use of a conventional technique, lyophilization (freeze drying) to form a suitable solution, stable solid from an unstable solution has met with only limited success apparently because of hydrolytic problems with the stannous ion.
Accordingly, it is an object of this invention to provide a soluble, stable product which upon the addition of a pertechnetate solution forms an effective bone-scanning agent.
In addition, it is a continuing object of all work in the bone scanning area to provide a product which exhibits high skeletal selectivity (i.e., high ratio of uptake on the skeleton to uptake in the soft tissues).